CN1354753A - Novel intermediates, process for preparing macrolide antibiotic agent therefrom - Google Patents
Novel intermediates, process for preparing macrolide antibiotic agent therefrom Download PDFInfo
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- CN1354753A CN1354753A CN99813690A CN99813690A CN1354753A CN 1354753 A CN1354753 A CN 1354753A CN 99813690 A CN99813690 A CN 99813690A CN 99813690 A CN99813690 A CN 99813690A CN 1354753 A CN1354753 A CN 1354753A
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- erythromycin
- oxime
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- 239000003120 macrolide antibiotic agent Substances 0.000 title abstract description 4
- 238000004519 manufacturing process Methods 0.000 title abstract 3
- 229940041033 macrolides Drugs 0.000 title abstract 2
- 239000000543 intermediate Substances 0.000 title 1
- 150000002923 oximes Chemical class 0.000 claims abstract description 44
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims abstract description 24
- 229960002626 clarithromycin Drugs 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 37
- 229960003276 erythromycin Drugs 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 229930006677 Erythromycin A Natural products 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- 238000010511 deprotection reaction Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- -1 trimethyl silyl Erythromycin A Chemical compound 0.000 claims description 9
- KYTWXIARANQMCA-RWJQBGPGSA-N (3r,4s,5s,6r,7r,9r,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecan-2 Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=NO)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-RWJQBGPGSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000003495 polar organic solvent Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 229950004288 tosilate Drugs 0.000 claims description 3
- WHGMHGPIJZTKTI-UHFFFAOYSA-N 3h-1,2-benzodithiole Chemical compound C1=CC=C2CSSC2=C1 WHGMHGPIJZTKTI-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 abstract description 6
- HQEVXECMYKMZLQ-UHFFFAOYSA-N 1,3-benzodithiole-2-sulfonic acid Chemical group C1=CC=C2SC(S(=O)(=O)O)SC2=C1 HQEVXECMYKMZLQ-UHFFFAOYSA-N 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 3
- WGHQUJVDEAGKKT-UHFFFAOYSA-N 1,3-benzodithiol-3-ium Chemical compound C1=CC=C2[S+]=CSC2=C1 WGHQUJVDEAGKKT-UHFFFAOYSA-N 0.000 abstract 1
- 230000000845 anti-microbial effect Effects 0.000 abstract 1
- 239000002244 precipitate Substances 0.000 abstract 1
- 239000011734 sodium Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001035 methylating effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HCMLNPZTRYNCMA-UHFFFAOYSA-N 1,3-benzodithiole Chemical compound C1=CC=C2SCSC2=C1 HCMLNPZTRYNCMA-UHFFFAOYSA-N 0.000 description 1
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical group CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a process for preparing a high yield of purified clarithromycin having broad antimicrobial activity as a macrolide antibiotic agent by using 1,3-benzodithiol-2-ylium tetrafluoroborate(BDFT), which can easily be synthesized from anthranilic acid and used as a protecting group for oxime. In addition, the present invention also provides a process for preparing clarithromycin from 1,3-benzodithiol-2-sulfonic acid group that forms clarithromycin salt which precipitates into crystals in reaction solution thereof, and purifying clarithromycin including a significantly simplified purification step.
Description
Invention field
The present invention relates to a kind of new preparation method by the clarithromycin shown in the following formula (I), said clarithromycin has broad spectrum antibiotic activity as macrolide antibiotics reagent, the invention still further relates to be used for the new intermediate of its synthetic.
The prior art background
So far, the preparation method of above-mentioned formula (I) compound is at Korean Patent notification number 91-5898,91-7572,91-2142,95-9367 and 96-434, Korean Patent Publication No. 90-18132 and 91-7953 and a lot of document, microbiotic magazine (Vol.46 for example, No.4,647 (1993)), microbiotic magazine (Vol.46, No.7,1163 (1993), microbiotic magazine (Vol.37, No.2,187 (1984)), heterogeneous ring compound (Vol.36, No.2,243 (1993)) and microbiotic magazine (Vol.43, No.3,286 (1990)) describe to some extent in.These methods can be aggregated into following three kinds of modes:
＜method 1 〉
This method comprise with carbobenzoxy-(Cbz) (Cbz) protect one of them OH group the erythromycin 9-9 oxime derivate that is protected 3 '-N; N-dimethylamino and 2 '-the OH group, the hydroxyl (referring to Korean Patent notification number 91-5898 and 91-7572) on the 6th of the said compound of methylating then.Yet the shortcoming of this method is to have to use excessive relatively Cbz-C1, even and implement deprotection by hydrogenation, this reaction also can't be finished fully because of paralyser.In addition, because in this method, 3 of said compound '-N, the methyl of N-dimethylamino need be regenerated by methylating in the final step of technology, thereby its additional defective is to be difficult to carry out, and the process time is long.This method can be represented by following path:
＜method 2 〉
This method comprise with similar group (for example, benzyl) quaternary salt protect one of them OH group the erythromycin 9-9 oxime derivate that is protected 3 '-N, N-dimethylamino (referring to Korean Patent notification number 91-2142).Because the deprotection in this method is also finished by using hydrogen as method 1, as method 1, reaction can't be finished fully because of paralyser.This method can be represented by following path:
＜method 3 〉
This method comprises the oxime of protecting erythromycin 9-9 oxime derivate with benzyl or ketal derivatives; and with substituted silyl protect 2 of said compound '-OH group and 4 '-the OH group; the 6-OH group of said compound then methylates; at last with the protecting group of the 9-oxime of said compound and said 2 '-the trimethyl silyl deprotection of O-and 4 '-O-group, obtain required compound (seeing Korean Patent notification number 95-9367 and 96-434) with relatively short step simultaneously.In this case, be used for 2 '-OH group and 4 '-the 9-9 oxime derivate of the trimethyl silylization of OH group should use with the form of non-salt.This method can be represented by following path:
According to above-mentioned response path, be about 45-50% from the productive rate of Erythromycin A synthetic clarithromycin.If in above-mentioned response path, protect oxime,, deprotection is difficult to carry out so long reaction owing to using hydrogen with benzyl derivative.Another shortcoming is to use excessive (about 2-3 equivalent) to be used to protect the ketal derivatives of oxime, and total reaction time is oversize.However, ketal derivatives and trimethyl silyl group can be eliminated simultaneously by acid treatment.
For eliminating the saprophytic material that produces in above-mentioned 3 kinds of synthesis techniques, include the purification step that the synthetic clarithromycin is separated out in the above-mentioned technology.Yet, in most of situation, productive rate about 10-20% that can descend.In addition, if the saprophytic material that exists during with the clarithromycin similar performance, it is very difficult eliminating saprophytic material.
Therefore, the present inventor has furtherd investigate the novel method of preparation required compound for solving the problem in the above-mentioned ordinary method and increasing output.Found that; by 1 shown in the following formula; 3-benzo dithiolane-2-base a tetrafluoro borate (1; 3-benzodithiol-2-yliumtetrafluoroborate) (BDTF) (synthesising communication; 471 (1976)) can be as the blocking group of oxime, and this BDTF can be synthetic simply from anthranilic acid.By developing the approach that new and simple high yield prepares clarithromycin, the present invention is achieved.
Summary of the invention
An object of the present invention is to provide a kind ofly by the Erythromycin A 9-O-BDT oxime intermediate shown in the following formula (III), it is suitable for synthetic clarithromycin, prepares by Erythromycin A 9-oxime or its hydrochloride and BDTF are reacted.
Wherein, Y
1And Y
2Expression hydrogen atom or trimethyl silyl.
In addition, the invention provides crystalline formula (III) compound (Y in the mixed solvent that contains 5-10 weight part acetone and 1-5 weight parts water
1And Y
2Be trimethyl silyl).The compound of said formula (III) is 2: 1 with the ratio of acetone.
In addition, another object of the present invention provides a kind of preparation method of clarithromycin, may further comprise the steps:
1) with Erythromycin A 9-oxime or its hydrochloride and the 1.0-1.2 normal 1 of following formula (II); 3-benzo dithiolane-2-base a tetrafluoro borate (BDTF) reacts in the proton inertia non-polar organic solvent in the presence of 1.0-2.0 equivalent pyridine; form following formula (III) ' Erythromycin A 9-O-BDT 9 oxime derivate; oximido group in this derivative is by benzo dithiolane (BDT) radical protection, shown in following response path:
Wherein, MC is a methylene dichloride,
2) with above-mentioned steps 1) synthetic formula (III) ' compound and the normal hexamethyl-disilazane of 3.0-5.0 (HMDS) react in the presence of such as the salt of ammonium chloride, pyridine hydrochloride, pyridine or tosilate, shown in the formation formula V 2 '-O, 4 " the two trimethylammoniums of O--silyl Erythromycin A 9-O-BDT 9 oxime derivate, shown in following response path:
3) with the normal methyl-iodide of 2.0-3.0 in the presence of alkaline in proton-inert polar solvent with above-mentioned steps 2) the 6-OH group of synthetic formula V compound methylates, 2 of formation following formula (VII) '-O, 4 " the two trimethyl silyls of O--6-oxygen-methyl-Erythromycin A 9-O-BDT 9 oxime derivate, shown in following response path:
4) with above-mentioned steps 3) synthetic formula (VII) compound deprotection, form following formula (I) BDSA compound, shown in following response path:
5) with step 4) synthetic formula (I) BDSA compound simple agitation in the mixed solvent of the organic solvent that water or water and water soluble mix, filter the formula (I) shown in the following path that forms then:
Detailed Description Of The Invention
Among the present invention; step 1 is by reacting the Erythromycin A 9-oxime shown in the above-mentioned formula of 1 equivalent (II) or its hydrochloride and the normal BDTF of 1-2 in the presence of 1.0-2.0 equivalent pyridine in the proton inertia non-polar organic solvent; form above-mentioned formula (III) ' Erythromycin A 9-O-BDT 9 oxime derivate finish; oximido in the wherein said derivative is rolled into a ball by 1,3-benzo dithiolane (BDT) radical protection.
Step 2 be by formula (III) ' compound that above-mentioned steps 1 is obtained and 3-5 equivalent hexa methyl silazane (HMDS) reaction in the presence of such as the salt of ammonium chloride, pyridine hydrochloride, pyridine or tosilate formation 2 shown in above-mentioned formula V '-O, 4 " O-pair of trimethylammoniums-silyl Erythromycin A 9-O-BDT 9 oxime derivate finished.
Among the present invention, methylating of above-mentioned formula V compound 6-OH group is to finish in 2: 2: 0.3 mixtures of 1: 1 mixture of proton-inert polar solvent (such as DMSO or DMF) or said proton-inert polar solvent and THF or said aprotic solvent, THF and non-polar organic solvent (such as isopropyl ether or tertiary butyl ethyl ether), wherein the amount of solvent be above-mentioned formula V compound 5-10 doubly so that form formula (VII).About 30 minutes to 2 hours of reaction cost must be at the normal Et of 0-2.5
3The normal highly basic of N, 1-3 such as NaH, alkoxide, KOH and NaOH and 2-3 equivalent methylating agent are to carry out under in-5 to 5 ℃ under the existence of methyl-iodide.
Then, with the compound deprotection of the above-mentioned formula of the present invention (VII), by using the normal formic acid (HCO of 1-3
2H) and the normal NaHSO of 4-8
3, Na
2SO
3, Na
2S
2O
4Or Na
2S
2O
5And the second alcohol and water ratio of 5-10 weight part is 1: 1 an ethanol/water mixed solvent reflux 4 hours.As a result, 1 of the clarithromycin shown in the synthetic above-mentioned formula (I), 3-benzo dithiolane-2-sulfonic acid (BDSA).
BDSA, by with blocking group BDT with take off oxime agent such as NaHSO
3, Na
2SO
3, Na
2S
2O
4Or Na
2S
2O
5Reaction and synthesize in the presence of HCOOH, when with 3 '-N, N-dimethylamino group in conjunction with the time, the form of its salt of reaction formation, BDSA represents by above-mentioned formula (I).Question response is finished and temperature is reduced to after the room temperature, will be in reaction solvent the required compound purifying of crystallization.As a result, make required compound and separating of other by product become easy.In this case, because the BDT group occurs in before the deprotection with the reaction of taking off between the oxime agent, oxime synthesizes under without any the prerequisite of protection.Take off the synthetic clarithromycin of result of oxime and in the end eliminate trimethyl silyl group in the step.
The method according to this invention, with following formula (1) BDSA and organic salt such as K
2CO
3, Na
2CO
3Or KOH reaction, so that in neutralization reaction, remove BDSA and finally obtain the pure crystallization of the clarithromycin of above-mentioned formula (I) expression.
Another object of the present invention provides the another kind of method of preparation formula (I) clarithromycin, by adding hexamethyl-disilazane (HMDS) to the Erythromycin A 9-oxime shown in the formula (II) or its hydrochloride, form 2 shown in the formula (IV) '-O, 4 " two trimethyl silyl-Erythromycin A 99 oxime derivates of O-; to replace above-mentioned step 1); and with 2 of formula (IV) '-O; 4 " the two trimethyl silyls of-O--Erythromycin A 9-9 oxime derivate reacts with 1-2 equivalent BDTF in proton-inert organic solvent such as MC in the presence of pyridine, form 2 shown in the formula V of certain output '-O, 4 " the two trimethyl silyl Erythromycin A 9-O-BDT 9 oxime derivates of O-; to replace above-mentioned step 2), shown in following response path:
After crystallization in the compound of above-mentioned formula V the mixed solvent (preferred ratio of mixture 3: 10), can obtain to contain the crystal solvent compound of 2: 1 above-mentioned formula V compounds and acetone at 5-10 weight parts water and 5-10 weight part acetone.
Following examples are with illustrated in greater detail the present invention, but they limit this never in any form
Scope of invention.
Embodiment 1 (1) preparation 2 '-O, 4 " the two trimethyl silyl Erythromycin A 9-oximes of O-
157g (0.2 mole) Erythromycin A 9-oxime hydrochloride and 5.4g (0.1 mole) ammonium chloride are put into 2 liters of flasks, and to the dimethyl formamide that wherein adds 600ml.217ml (mole) hexamethyl-disilazane (HMDS) is slowly added in the mixture, stirred 3 hours down at 35-40 ℃ then.Add 30ml water to mixture, stirred then one hour.Afterwards, add 600ml water again.After the further stirring of mixture 30 minutes, add 150ml 2N-NaOH, use 600ml dichloromethane extraction mixture then.The aqueous solution layer is used 2 liters of dichloromethane extraction again.Merge after the organic layer, with 200ml saturated brine solution purging compound, then through anhydrous MgSO
4Dehydration.Solvent is removed in decompression, obtains 170.5g spumescence title compound (productive rate 95.4%).
1H NMR (CDCl
3) δ 0.16 (s, 9H ,-OTMS), 0.19 (s, 9H ,-OTMS) (2a) preparation 2 '-O, 4 " the two trimethyl silyls of O--Erythromycin A 9-O-BDT oxime
With 8.93g (10 mmole) above-mentioned 1) preparation 2 '-O, 4 " the two trimethyl silyls of O--Erythromycin A 9-oxime is dissolved in the 40ml methylene dichloride, adds 2.52g (1.05 mmole) BDTF down at 20-25 ℃ then.In mixture, slowly add 1.13ml (14 mmole) pyridine, stirred then 30 minutes.Add 50ml methylene dichloride and 50ml water to mixture, extract then.Wash organic layer with saturated brine solution, through anhydrous MgSO
4Dehydration is filtered, the dry then 10.25g spumescence title compound (productive rate 98.0%) that obtains.
1H NMR (CDCl3) δ 7.37 (m, 2H), 7.11 (m, 2H), 6.88 (s, 1H), 3.28 (s.3H), 2.63 (s, 6H), 0.16 (s, 18H) ratio of (2b) preparation oxime and acetone be 2: 12 '-O-, the 4 " solvates of O-couple of trimethyl silyl Erythromycin A 9-O-BDT
The water of 30.75ml is slowly added in the required compound of above-mentioned form of foam, and wherein said compound has been dissolved in 102.5ml acetone.Then, the solid of gained is put into ice bath, stirred 1 hour, filter and drying.As a result, the ratio of acquisition oxime and acetone is the solvate of 2: 1 the two trimethyl silyl-Erythromycin A 9 O-BDT 8.95g (85.0% productive rate) of 2 " O-, " 4-O-.
1H-NMR (CDCl
3) δ 7.37 (m, 2H), 7.11 (m, 2H), 6.88 (s.mH), 3.28 (s, 3H), 2.63 (s, 6H), 2.10 (s, 6H), 0.16 (s, 18H) (3) preparation 2 '-O-, 4 " the two trimethyl silyls of O--6-oxygen-methyl-Erythromycin A 9 O-BDT oximes
With 10.45g (10 mmole) above-mentioned 2) preparation 2 '-O, 4 " before the two trimethyl silyl Erythromycin A 9-O-BDT oximes of O-add in the mixture of the anhydrous THF of 160ml, anhydrous DMSO and t-butyl methyl ether (2: 2: 0.3), add 1.39lml Et3N to mixture.Temperature is adjusted to 0 ℃.This moment, to wherein adding 0.98g (15 mmole) KOH and 1.25ml (20 mmole) methyl-iodide.Wait to stir after the mixture 1 hour, reaction is finished.Afterwards, with mixture order 100ml hexane and 100ml water extraction.With about 10% salt brine solution washing organic layer, through anhydrous MgSO
4Dehydration is filtered then.Removal of solvent under reduced pressure obtains the foamed required compound of 10.46g (productive rate 98.8%).
1H NMR (CDCl
3) δ 7.05-7.40 (m, 4H), 6.89 (s, 1H), 3.31 (s, 3H), 2.63 (s, 3H), 2.22 (s, 6H), 0.17 (s, 9H) .0.09 (s, 9H) (4) preparation 1,3-benzo dithiolane-2-sulfonate
With 10.60g (10 mmole) above-mentioned 3) preparation 2 '-O-, 4 " the two trimethyl silyls of O--6-O-erythromycin A 9-O-BDT oxime is dissolved in 50ml ethanol, then to wherein adding 50ml water.With 0.57ml (15 mmole) formic acid and 4.16g (40 mmole) sodium bisulfite (NaHSO
3) add in the mixture and reflux 2 hours.Adding 0.19ml (0.5 mmole) formic acid more in addition in reaction mixture also refluxed 2 hours again.After reaction is finished, the temperature of reaction mixture is dropped to room temperature, with the solid filtering that obtains, drying obtains the required compound of 5.80g (59.1% productive rate).
1H NMR (CDCl
3+ DMSO-d
6) δ 7.18 (M, 2H), 7.01 (m, 2H), 5.61 (s, 1H), 5.05 (d, 1H), 4.89 (d, 1H), 4.55 (d, 1H), 3.97 (m, 2H), 3.70 (m, 5H), 3.40 (m, 2H), 3.32 (s, 3H), 3.02 (s, 8H), 2.83 (dd, 6H), 2.59 (m, 1H), 2.34 (d, 1H), 1.40-1.95 (m, 6H), 1.37 (s, 3H), 1.10-1.35 (m, 26H), 0.85 (t, 3H) (5) preparation clarithromycin
The compound that 9.82g (10 mmole) above-mentioned steps 4 is obtained adds in 19.64ml ethanol and the 49.1ml water and stirring.To be dissolved in the 2.76g K of 49.1ml water
2CO
3Slowly add in the mixture.The crystal of gained is put into the 14mg K that is dissolved in 98.2ml water
2CO
3In and stirred 5 minutes, filter and dry, obtain 7.14g (95.5% productive rate) required compound.
1H-NMR(CDCl
3)δ5.08(d，1H)，4.93(d，1H)，4.44(d，1H)，4.02(m，1H)3.99(s，1H)，3.78(m，2H)，3.67(d，1H)，3.33-3.46(m，2H)，3.34(s，3H)，3.19(t，2H)，3.06(s，3H)，2.89-3.02(m，2H)，2.89(m，1H)，2.58(m，1H)，2.40(m，2H)，2.29(s，6H)，1.93(d，1H)，1.40-1.95(m，6H)，1.42(s，3H)，1.10-1.35(m，26H)，0.85(t，3H)
Embodiment 2
Press the same procedure of embodiment 1, obtain 10.33g (97.5% productive rate) 2 '-O-, 4 " the two trimethyl silyl Erythromycin A 9-O BDT oxime compounds of O-, difference is with the KOH in 0.8g (20 mmole) 60%NaH replacement the foregoing description 1 step (3).
Embodiment 3
7.49g (10 mmole) Erythromycin A 9-O-oxime is dissolved in the 40ml methylene dichloride, and adds 1.13ml (14 mmole) pyridine.At room temperature add 2.64g (11 a mmole) BDTF to mixture by part, uniform temp stirred 30 minutes down then.After question response is finished, 40ml methylene dichloride and 60ml water are added in the mixture, extract then.Organic layer washs with 10% salt brine solution, through anhydrous MgSO
4Dehydration is filtered then.Removal of solvent under reduced pressure, the required compound (productive rate 97.2%) of acquisition 8.76g form of foam.All the other processes are carried out according to the same way as of embodiment 1 step (2).
1H?NMR(CDCl
3)δ7.30(m，2H)，7.13(m，2H)，6.87(s，1H)，3.30(s，3H)，2.50(s，6H)
Embodiment 4
Press step (2) and embodiment 3 and 4 preparation 9.01g (10 mmole) the Erythromycin A 9-O-BDT oximes of embodiment 1, and 0.8g (15 mmole) ammonium chloride is added in the 27ml dimethyl formamide.8.44ml (40 mmole) hexamethyl-disilazane (HMDS) is slowly added in the mixture, stirred 5 hours down at 40-50 ℃ then.The mixture order with 60ml water and 60ml dichloromethane extraction, and is used the 20ml dichloromethane extraction with water layer again.Merge organic layer, with the washing of 20ml saturated brine solution, then through anhydrous MgSO
4Dehydration.Removal of solvent under reduced pressure, the required compound (productive rate 91.2%) of acquisition 9.53g form of foam.All the other processes are carried out according to the same way as of embodiment 1 step (3).Embodiment 5
Same procedure according to embodiment 1 obtains 5.67g (57.7% productive rate) 1,3-benzo dithiolane-2-sulfonic acid, and difference is the Na with 8.2g (40 mmole)
2S
2O
4Replace the NaHSO in the foregoing description 1 step (4)
3
Embodiment 6
Same procedure according to embodiment 1 obtains 5.49g (55.9% productive rate) 1,3-benzo dithiolane-2-sulfonic acid, and difference is with 7.84g (40 mmole) Na
2S
2O
5Replace the NaHSO in the foregoing description 1 step (4)
3
Embodiment 7
Same procedure according to embodiment 1 obtains 5.62g (57.2% productive rate) of 1,3-benzo dithiolane-2-sulfonic acid, and difference is with 5.04g (40 mmole) Na
2S
2O
3Replace the NaHSO in the foregoing description 1 step (4)
3
Be effect of the present invention below:
At first, in the prior art, use benzyl derivative to make difficulty in process as the blocking group of oxime, this is because deprotection must be finished by the hydrogenation that uses catalyzer, and reaction can't be finished deprotection fully because of paralyser.In addition, when use ketal derivatives as the deprotection process in during the blocking group of oxime, advantage is to make trimethyl silyl group and oxime deprotection simultaneously.Yet, also have some shortcomings, prolong such as excessive use ketal derivatives and reaction times.Yet according to the present invention, the protection of oxime can be by using 1, and 3-benzo dithiolane-2-base a tetrafluoro borate (BDTF) is to finish easily near quantitative mode, and wherein BDTF can be synthetic simply by anthranilic acid.In addition; because said BDTF group as the oxime blocking group can be removed with trimethyl silyl group and oximido group; thereby when deprotection is finished under acidic conditions; technology can be simplified, and formula (I) required compound of about 52% productive rate can be obtained by the short-term method of using this utilization Erythromycin A.
Secondly, in the prior art,, thereby cause the about 10-20% of productive rate decline because the crystalline step must be come the purest form of purifying clarithromycin after deprotection in ethanol.Yet; in the present invention; the formation of salt obtains BDSA and combine and finish by deprotection being obtained clarithromycin and protecting group and taking off between the oxime agent reaction, and reaction mixture is cooled to is fit to salt intermediate crystalline room temperature, so that the separation crystal of pure form.
So, after eliminating salt, can obtain the clarithromycin of high purity and high yield, and purification step can obtain obviously simplifying by neutralization.
The 3rd, the blocking group of oxime only has protected oxime in the prior art, and allows the selectivity of introducing methyl group.The BDTF group that uses among the present invention not only can be protected oxime and allow selectivity, and can by with such as NaHSO
3, Na
2SO
3, Na
2S
2O
4Or Na
2S
2O
5The oxime agent reaction of taking off form the BDSA group and form clarithromycin salt, this salt can directly extract as crystal from reaction mixture, thus explanation can be simplified purification step significantly effectively.
Claims (8)
- One kind be suitable for synthetic clarithromycin by the Erythromycin A 9-O-benzo dithiolane oxime intermediate shown in the following formula (III), this intermediate passes through Erythromycin A 9-oxime or its hydrochloride and 1, and 3-benzo dithiolane-2-base a tetrafluoro borate (BDTF) reaction prepares:
Wherein, Y 1And Y 2Be hydrogen atom or trimethyl silyl. - 2. the intermediate of claim 1 is wherein with the compound (Y of following formula (III) 1And Y 2Be trimethyl silyl) crystallization in the mixed solvent that contains 5-10 weight part acetone and 1-5 weight parts water, and the ratio of the crystal solvent compound that contains said formula (III) compound of gained and acetone is 2: 1.
- 3. the preparation method of clarithromycin shown in the formula (I) may further comprise the steps:1) with Erythromycin A 9-oxime or its hydrochloride and the 1.0-1.2 normal 1 of following formula (II); 3-benzo dithiolane-2-base a tetrafluoro borate (BDTF) reacts in the proton inertia non-polar organic solvent in the presence of 1.0-2.0 equivalent pyridine; form following formula (III) ' Erythromycin A 9-O-BDT 9 oxime derivate; oximido group in this derivative is by benzo dithiolane (BDT) radical protection, shown in following response path:
Wherein, MC is a methylene dichloride,2) with above-mentioned steps 1) synthetic formula (III) ' compound and the normal hexamethyl-disilazane of 3.0-5.0 (HMDS) react in the presence of such as the salt of ammonium chloride, pyridine hydrochloride, pyridine or tosilate, shown in the formation formula V 2 '-O, 4 " the two trimethylammoniums of O--silyl Erythromycin A 9-O-BDT derivative, shown in following response path:
3) with the normal methyl-iodide of 2.0-3.0 in the presence of alkaline in proton-inert polar solvent with above-mentioned steps 2) the 6-OH group of synthetic formula V compound methylates, 2 of formation following formula (VII) '-O, 4 " the two trimethyl silyls of O--6-O-methyl-Erythromycin A 9-O-BDT 9 oxime derivate, shown in following response path:
4) with above-mentioned steps 3) synthetic formula (VII) compound deprotection, form following formula (I) BSDA compound, shown in following response path:
5) with above-mentioned steps 4) synthetic formula (I) BDSA compound stirring in the mixed solvent of the organic solvent that water or water and water soluble mix in the presence of a kind of inorganic salt, filtering then and form formula (I) clarithromycin shown in the following path: - 4. the method for claim 3, comprise adding hexamethyl-disilazane (HMDS) to Erythromycin A 9-oxime or its hydrochloride and forming shown in the formula (IV) 2 '-O, 4 " step of two trimethyl silyl-Erythromycin A 99 oxime derivates of O-; to replace above-mentioned step 1); and with 2 of said formula (IV) '-O; 4 " the two trimethyl silyls of-O--Erythromycin A 9-9 oxime derivate reacts with BDTF in proton-inert organic solvent in the presence of pyridine, shown in the formation formula V 2 '-O, " step of the two trimethyl silyl Erythromycin A 9-O-BDT 9 oxime derivates of O-; to replace above-mentioned step 2), shown in following response path:
- 5. the method for claim 3, wherein above-mentioned steps 3) to methylate be to finish in 2: 2: 0.3 mixtures of 1: 1 mixture by use proton-inert polar solvent such as DMF or DMSO, said proton-inert polar solvent and THF or said aprotic solvent, THF and non-polar organic solvent such as isopropyl ether or t-butyl methyl ether down at-5 to 5 ℃, wherein the amount of solvent be the formula V compound 5-10 doubly, with the normal highly basic of 1.0-3.0 such as KOH, alkoxide and NaH and the normal methyl-iodide of 2.0-3.0 as methylating agent at the normal Et of 0-2.5 3Under existing, N carries out reaction in 30 minutes to 2 hours.
- 6. the method for claim 3, wherein above-mentioned steps 5) in the solvable machine solvent that is mixed be methyl alcohol or ethanol.
- 7. the method for claim 3, wherein the deprotection of step 4) is by using normal formic acid of 1.0-3.0 and the normal NaHSO of 4.0-8.0 3, Na 2S 2O 4, Na 2S 2O 5Or Na 2SO 3In mixture finish at 1: 1 at the second alcohol and water of 5-10 weight part, and before crystallization, be cooled to room temperature.
- 8. the method for claim 3, wherein above-mentioned steps 5) neutralization procedure be by preparing the solution of above-mentioned formula (I) BDSA compound, and add the solvent that the 3-5 weight part contains 1-2 weight part inorganic salt to said solution and finish, the solution of wherein said formula (I) BDSA compound is by mixing with the said compound of 1 weight part and 10-20 weight parts water or with 5-10 weight parts water and 5-10 weight part methyl alcohol or 1: 1 mixture of alcoholic acid.
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|---|---|---|---|
| KR19980050425 | 1998-11-24 | ||
| KR1998/50425 | 1999-11-16 | ||
| KR1999/50802 | 1999-11-16 | ||
| KR1019990050802A KR100317907B1 (en) | 1998-11-24 | 1999-11-16 | Novel Intermediates, process for preparing macrolide antibiotic agent therefrom |
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| EP (1) | EP1133511B1 (en) |
| JP (1) | JP3848837B2 (en) |
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| AT (1) | ATE234321T1 (en) |
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| CN103080122A (en) * | 2010-03-22 | 2013-05-01 | 森普拉制药公司 | Crystalline forms of a macrolide, and uses therefor |
| US9051346B2 (en) | 2010-05-20 | 2015-06-09 | Cempra Pharmaceuticals, Inc. | Process for preparing triazole-containing ketolide antibiotics |
| US9072759B2 (en) | 2008-10-24 | 2015-07-07 | Cempra Pharmaceuticals, Inc. | Biodefenses using triazole-containing macrolides |
| US9200026B2 (en) | 2003-03-10 | 2015-12-01 | Merck Sharp & Dohme Corp. | Antibacterial agents |
| US9453042B2 (en) | 2007-10-25 | 2016-09-27 | Cempra Pharmaceuticals, Inc. | Process for the preparation of macrolide antibacterial agents |
| US9480679B2 (en) | 2009-09-10 | 2016-11-01 | Cempra Pharmaceuticals, Inc. | Methods for treating malaria, tuberculosis and MAC diseases |
| US9751908B2 (en) | 2013-03-15 | 2017-09-05 | Cempra Pharmaceuticals, Inc. | Convergent processes for preparing macrolide antibacterial agents |
| US9815863B2 (en) | 2010-09-10 | 2017-11-14 | Cempra Pharmaceuticals, Inc. | Hydrogen bond forming fluoro ketolides for treating diseases |
| US9861616B2 (en) | 2013-03-14 | 2018-01-09 | Cempra Pharmaceuticals, Inc. | Methods for treating respiratory diseases and formulations therefor |
| US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
| US10188674B2 (en) | 2012-03-27 | 2019-01-29 | Cempra Pharmaceuticals, Inc. | Parenteral formulations for administering macrolide antibiotics |
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| ES2221807B1 (en) * | 2003-06-24 | 2005-12-16 | Ercros Industrial, S.A. | A PROCEDURE FOR OBTAINING CLARITROMYCIN. |
| US7767797B1 (en) * | 2004-09-30 | 2010-08-03 | Synovo Gmbh | Macrocyclic compounds and methods of use thereof |
| US7582611B2 (en) * | 2005-05-24 | 2009-09-01 | Pfizer Inc. | Motilide compounds |
| EP1904041A2 (en) * | 2005-07-07 | 2008-04-02 | Elan Pharma International Limited | Nanoparticulate clarithromycin formulations |
| US20090054634A1 (en) * | 2007-08-09 | 2009-02-26 | Vinod Kumar Kansal | Process for the preparation of clarithromycin |
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| US5872229A (en) * | 1995-11-21 | 1999-02-16 | Abbott Laboratories | Process for 6-O-alkylation of erythromycin derivatives |
| US5719272A (en) * | 1996-04-02 | 1998-02-17 | Abbott Laboratories | 2'-protected 3'-dimethylamine, 9-etheroxime erythromycin A derivatives |
| US5864023A (en) * | 1997-02-13 | 1999-01-26 | Abbott Laboratories | 3'-N'oxide, 3'-n-dimethylamine, 9-oxime erythromycin a derivatives |
| US5929219A (en) * | 1997-09-10 | 1999-07-27 | Abbott Laboratories | 9-hydrazone and 9-azine erythromycin derivatives and a process of making the same |
| WO1999028333A1 (en) * | 1997-12-01 | 1999-06-10 | Abbott Laboratories | Chemical synthesis of 6-o-alkyl erythromycin c |
| ES2177448B1 (en) * | 1997-12-22 | 2004-08-01 | Biochemie S.A. | "OXYM OF ERYTHROMYCIN A.". |
| AU2658899A (en) * | 1998-02-04 | 1999-08-23 | Teva Pharmaceutical Industries Ltd. | Process for making clarithromycin |
-
1999
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| US10131684B2 (en) | 2007-10-25 | 2018-11-20 | Cempra Pharmaceuticals, Inc. | Process for the preparation of macrolide antibacterial agents |
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| US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
| US9480679B2 (en) | 2009-09-10 | 2016-11-01 | Cempra Pharmaceuticals, Inc. | Methods for treating malaria, tuberculosis and MAC diseases |
| CN103080122A (en) * | 2010-03-22 | 2013-05-01 | 森普拉制药公司 | Crystalline forms of a macrolide, and uses therefor |
| US9051346B2 (en) | 2010-05-20 | 2015-06-09 | Cempra Pharmaceuticals, Inc. | Process for preparing triazole-containing ketolide antibiotics |
| US9815863B2 (en) | 2010-09-10 | 2017-11-14 | Cempra Pharmaceuticals, Inc. | Hydrogen bond forming fluoro ketolides for treating diseases |
| US10188674B2 (en) | 2012-03-27 | 2019-01-29 | Cempra Pharmaceuticals, Inc. | Parenteral formulations for administering macrolide antibiotics |
| US9861616B2 (en) | 2013-03-14 | 2018-01-09 | Cempra Pharmaceuticals, Inc. | Methods for treating respiratory diseases and formulations therefor |
| US9751908B2 (en) | 2013-03-15 | 2017-09-05 | Cempra Pharmaceuticals, Inc. | Convergent processes for preparing macrolide antibacterial agents |
Also Published As
| Publication number | Publication date |
|---|---|
| IL143331A0 (en) | 2002-04-21 |
| ES2190275T3 (en) | 2003-07-16 |
| TR200101474T2 (en) | 2001-12-21 |
| WO2000031099A1 (en) | 2000-06-02 |
| KR20000057013A (en) | 2000-09-15 |
| AU1584700A (en) | 2000-06-13 |
| US6600025B1 (en) | 2003-07-29 |
| MXPA01005248A (en) | 2003-08-19 |
| CA2352162A1 (en) | 2000-06-02 |
| DE69905935T2 (en) | 2003-09-04 |
| HUP0104600A2 (en) | 2002-03-28 |
| DK1133511T3 (en) | 2003-07-14 |
| EP1133511A1 (en) | 2001-09-19 |
| KR100317907B1 (en) | 2001-12-24 |
| RU2208615C2 (en) | 2003-07-20 |
| HUP0104600A3 (en) | 2003-12-29 |
| AU751874B2 (en) | 2002-08-29 |
| CZ20011803A3 (en) | 2001-10-17 |
| ATE234321T1 (en) | 2003-03-15 |
| EP1133511B1 (en) | 2003-03-12 |
| DE69905935D1 (en) | 2003-04-17 |
| PT1133511E (en) | 2003-06-30 |
| PL348607A1 (en) | 2002-06-03 |
| JP3848837B2 (en) | 2006-11-22 |
| BR9915646A (en) | 2001-08-07 |
| JP2002530423A (en) | 2002-09-17 |
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